Clark Jennifer, Freeman Jessica, Donninger Howard
Molecular Targets Program, Department of Medicine, James Graham Brown Cancer Center, University of Louisville, 505 S. Hancock Street, Louisville, KY 40202, USA.
Mol Biol Int. 2012;2012:705948. doi: 10.1155/2012/705948. Epub 2012 May 24.
RASSF2 is a novel pro-apoptotic effector of K-Ras that is frequently inactivated in a variety of primary tumors by promoter methylation. Inactivation of RASSF2 enhances K-Ras-mediated transformation and overexpression of RASSF2 suppresses tumor cell growth. In this study, we confirm that RASSF2 and K-Ras form an endogenous complex, validating that RASSF2 is a bona fide K-Ras effector. We adopted an RNAi approach to determine the effects of inactivation of RASSF2 on the transformed phenotype of lung cancer cells containing an oncogenic K-Ras. Loss of RASSF2 expression resulted in a more aggressive phenotype that was characterized by enhanced cell proliferation and invasion, decreased cell adhesion, the ability to grow in an anchorage-independent manner and cell morphological changes. This enhanced transformed phenotype of the cells correlated with increased levels of activated AKT, indicating that RASSF2 can modulate Ras signaling pathways. Loss of RASSF2 expression also confers resistance to taxol and cisplatin, two frontline therapeutics for the treatment of lung cancer. Thus we have shown that inactivation of RASSF2, a process that occurs frequently in primary tumors, enhances the transforming potential of activated K-Ras and our data suggests that RASSF2 may be a novel candidate for epigenetic-based therapy in lung cancer.
RASSF2是K-Ras一种新的促凋亡效应因子，在多种原发性肿瘤中常因启动子甲基化而失活。RASSF2失活增强K-Ras介导的转化作用，而RASSF2过表达则抑制肿瘤细胞生长。在本研究中，我们证实RASSF2与K-Ras形成内源性复合物，验证了RASSF2是一种真正的K-Ras效应因子。我们采用RNA干扰方法来确定RASSF2失活对含有致癌性K-Ras的肺癌细胞转化表型的影响。RASSF2表达缺失导致更具侵袭性的表型，其特征为细胞增殖和侵袭增强、细胞黏附性降低、非锚定依赖性生长能力以及细胞形态改变。细胞这种增强的转化表型与活化的AKT水平升高相关，表明RASSF2可调节Ras信号通路。RASSF2表达缺失还赋予细胞对紫杉醇和顺铂这两种肺癌一线治疗药物的抗性。因此，我们表明RASSF2失活（这一过程在原发性肿瘤中频繁发生）增强了活化K-Ras的转化潜能，并且我们的数据表明RASSF2可能是肺癌基于表观遗传学治疗的新候选靶点。
